About NF2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF2 c.604G>T, p.(Glu202Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
NM_000268.3:c.604G>T is a nonsense variant (p.Glu202Ter) in exon 7 of 16 coding exons in NF2, a tumor suppressor gene where loss-of-function is an established germline disease mechanism for NF2-related schwannomatosis. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with confirmed LoF disease mechanism are assigned PVS1 at very strong strength. NMD is predicted as the premature termination codon (position 202 of 596) occurs more than 50 nucleotides upstream of the last exon junction.
PM1Moderate
PM1 · moderate
The nonsense variant p.Glu202Ter truncates merlin within the FERM domain (residues ~1-300), a well-characterized functional domain essential for membrane association and tumor suppressor activity. The premature stop at codon 202 removes the F3 lobe of the FERM domain and all downstream domains, including the alpha-helical and C-terminal regions. The FERM domain is established as critical for merlin function through extensive literature on NF2 pathogenesis.
PM2Moderate
PM2 · moderate
NM_000268.3:c.604G>T is absent from gnomAD v2.1 (~141,456 individuals), gnomAD v4.1 (~807,162 individuals), and gnomAD-Canada v1.0. Under generic ACMG, PM2 applies for variants with population frequency <0.1% that are absent from large population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM1 moderate, PM2 moderate; combination = 1 very strong + 2 moderate, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.140 maximum delta
Recorded SpliceAI maximum delta score: 0.140. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58526910, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 3 met · 7 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000268.3:c.604G>T (p.Glu202Ter) is a nonsense variant in exon 7 of NF2, creating a premature termination codon predicted to trigger nonsense-mediated decay or produce a severely truncated merlin protein lacking the FERM domain F3 lobe and all downstream domains.
NF2 is a well-established tumor suppressor gene where germline loss-of-function variants cause NF2-related schwannomatosis, an autosomal dominant tumor predisposition syndrome characterized by bilateral vestibular schwannomas, meningiomas, and other nervous system tumors.
Truncating NF2 mutations, including nonsense variants, are associated with a more severe disease phenotype with earlier age of onset compared to missense or splice site mutations, as demonstrated in the largest genotype-phenotype study of 125 NF2 families.
The variant is absent from gnomAD v2.1 (~141,456 individuals) and gnomAD v4.1 (~807,162 individuals), consistent with a rare disease-causing variant not tolerated in the general population.
The premature stop at codon 202 occurs within the FERM domain, a critical functional domain required for merlin membrane association and tumor suppressor activity; the truncation removes the F3 subdomain and all C-terminal domains essential for merlin-mediated growth regulation.
Combined evidence satisfies ACMG/AMP Pathogenic classification: PVS1 (Very Strong) + PM2 (Moderate) + PM1 (Moderate).
No criteria match.
Met · 3
PVS1 Very strongNM_000268.3:c.604G>T is a nonsense variant (p.Glu202Ter) in exon 7 of 16 coding exons in NF2, a tumor suppressor gene where loss-of-function is an established germline disease mechanism for NF2-related schwannomatosis. Under the ClinGen SVI PVS1 framework (PMC6185798), nonsense variants in genes with confirmed LoF disease mechanism are assigned PVS1 at very strong strength. NMD is predicted as the premature termination codon (position 202 of 596) occurs more than 50 nucleotides upstream of the last exon junction. Details ▾Hide ▴
Evidence considered
- Nonsense variant p.(Glu202Ter) creates a premature termination codon at amino acid 202 of 596
- NF2 loss-of-function is an established mechanism for NF2-related schwannomatosis
- supported by multiple germline disease publications
- Variant is in exon 7 of 16 coding exons
- NMD is predicted
- No CSPEC/VCEP exists for NF2
- generic PVS1 framework (PMC6185798) applied
Sources
PM1 ModerateThe nonsense variant p.Glu202Ter truncates merlin within the FERM domain (residues ~1-300), a well-characterized functional domain essential for membrane association and tumor suppressor activity. The premature stop at codon 202 removes the F3 lobe of the FERM domain and all downstream domains, including the alpha-helical and C-terminal regions. The FERM domain is established as critical for merlin function through extensive literature on NF2 pathogenesis. Details ▾Hide ▴
Evidence considered
- Merlin FERM domain (residues ~1-300) is critical for membrane localization and tumor suppressor function
- Truncation at codon 202 removes the FERM F3 lobe and all downstream domains
- PMID:9643284 demonstrates truncating NF2 mutations are associated with severe disease phenotype
Sources
PM2 ModerateNM_000268.3:c.604G>T is absent from gnomAD v2.1 (~141,456 individuals), gnomAD v4.1 (~807,162 individuals), and gnomAD-Canada v1.0. Under generic ACMG, PM2 applies for variants with population frequency <0.1% that are absent from large population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles observed)
- Absent from gnomAD v4.1 (0 alleles observed)
- Absent from gnomAD-Canada v1.0 (0 alleles observed)
Sources
Not met · 7 · evaluated, threshold not reached
PS3 No variant-specific functional studies were identified for p.Glu202Ter or for a systematically characterized range that includes codon 202. OncoKB's 'Likely Loss-of-function' label is a bioinformatic prediction, not experimental functional data. No publication tested this variant or a saturated range encompassing it in a functional assay. Details ▾Hide ▴
Evidence considered
- OncoKB annotation of Likely Loss-of-function is computational
- not experimental evidence for PS3
- No variant-specific or range-specific functional assays found in any reviewed publication
Still missing
- No experimental functional data exists for this variant
PS4 The variant is absent from gnomAD population databases, but no clinical cohort or case series reporting this specific variant in affected individuals was identified. COSMIC reports n=2 somatic occurrences, but germline prevalence data in NF2-affected cohorts is unavailable. Details ▾Hide ▴
Evidence considered
- COSMIC COSV58526910: n=2 somatic occurrences only
- no germline case data
Still missing
- No germline clinical cohort data for this specific variant
PP5 ClinVar VariationID 3231107 is associated with NM_000268.4:c.718G>T (p.Gly240Trp), NOT NM_000268.3:c.604G>T (p.Glu202Ter). The ClinVar match is not an exact match for this variant. The classification is 'Uncertain significance, criteria provided, single submitter' from Ambry Genetics — even if it were the correct variant, it is not from an expert panel and does not meet the 3-star EP threshold. PP5 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3231107 is for NM_000268.4:c.718G>T (p.Gly240Trp)
- a different variant
- Classification is Uncertain significance
- single submitter — does not meet PP5 evidentiary threshold even if it were the correct variant
Still missing
- No ClinVar entry exists for the specific variant NM_000268.3:c.604G>T
BA1 The variant is absent from gnomAD v2.1 and v4.1. BA1 requires allele frequency >1% in population databases, which is not met. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD (0% frequency
- far below 1% BA1 threshold)
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1. BS1 requires allele frequency >0.3% in population databases, which is not met. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD (0% frequency
- far below 0.3% BS1 threshold)
Sources
BS3 No well-established functional studies demonstrating no deleterious effect were identified for p.Glu202Ter. OncoKB suggests Likely Loss-of-function, consistent with a deleterious rather than benign effect. No publication reports experimental data showing normal protein function for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB annotation suggests deleterious (Likely Loss-of-function)
- inconsistent with BS3
- No benign functional data found in any reviewed publication
Still missing
- No functional studies testing this variant for benign effect
BP6 ClinVar VariationID 3231107 is associated with NM_000268.4:c.718G>T (p.Gly240Trp), NOT this variant. No reputable source reports this specific variant as benign or likely benign. Even the matched ClinVar record is classified as Uncertain significance, which does not support BP6. Details ▾Hide ▴
Evidence considered
- No ClinVar entry exists for the specific variant NM_000268.3:c.604G>T
- The closest ClinVar match (VariationID 3231107) is for a different variant and is classified as Uncertain significance
Still missing
- No ClinVar entry for the specific variant
Not assessed · 8 · no assessment recorded
PS2 No de novo data is available in the case materials for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data or parental genotype information available
PM6 No de novo data is available for this variant in the case materials. Details ▾Hide ▴
Still missing
- No de novo confirmation available
PP1 No family segregation data is available for this variant. Details ▾Hide ▴
Still missing
- No cosegregation data available
PP4 No patient phenotype data is available in the case materials to assess whether the clinical presentation is specific for NF2-related schwannomatosis. Details ▾Hide ▴
Still missing
- No patient phenotype information provided
BS2 No data available on observation of this variant in healthy adults. BS2 requires observation in a healthy adult with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No healthy adult observation data available
BS4 No cosegregation data is available. BS4 requires lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No data on in trans observation with a known pathogenic variant is available. Details ▾Hide ▴
Still missing
- No in trans phase data available
BP5 No data available on this variant being observed in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when the same amino acid change has been established as pathogenic; this is a nonsense (stop-gain) variant, not a missense change amenable to PS1 evaluation. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies when a different missense change at the same residue has been classified as pathogenic. This variant is a nonsense (stop-gain) change producing p.Glu202Ter; PM5 is not applicable to nonsense variants because the pathogenic mechanism (protein truncation via NMD) differs fundamentally from missense alterations. Additionally, no ClinVar comparator variants at codon 202 were identified with pathogenic classification. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense (stop-gain) variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
PP3 N/APP3 evaluates in silico predictions of deleterious effect for missense variants. This is a nonsense variant; protein-truncating effect is self-evident from the variant type and in silico pathogenicity prediction does not add independent evidence. Per PMC6185798, PP3 should not be stacked with PVS1 for variants where the deleterious mechanism is already captured by the variant type. Details ▾Hide ▴
Evidence considered
- BayesDel score 0.66 noted but not applicable to PP3 for a truncating variant
- SpliceAI max delta 0.14 confirms no cryptic splice effect
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is itself a truncating (nonsense) variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 evaluates in silico predictions suggesting no impact for missense or splice variants. This is a nonsense variant where the protein-truncating effect is self-evident; in silico tools are not designed to assess stop-gain variants. SpliceAI max delta score of 0.14 indicates no cryptic splice effect, but BP4 does not apply to nonsense variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.14 indicates no significant splice alteration
- BayesDel 0.66 not applicable to nonsense variant assessment
BP7 N/AThis is a nonsense variant. BP7 applies to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard ACMG/AMP criterion; likely intended for PS5 alternative applications. This variant does not fit any recognized PS5 use case. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NF2
- Transcript
- NM_000268.3
- Coding (HGVS c.)
- NM_000268.3:c.604G>T
- Protein (HGVS p.)
- NP_000259.1:p.(Glu202Ter)
- GRCh38
- chr22:29658193 G>T
- GRCh37
- chr22:30054182 G>T
- ClinVar
- 3231107
- COSMIC
- COSV58526910
Gene diagram
Every interpreted variant in NF2, mapped onto the exon structure of NM_000268.3. Select a row to find it on the plot.
NF2NM_000268.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NF2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 N/APP3 evaluates in silico predictions of deleterious effect for missense variants. This is a nonsense variant; protein-truncating effect is self-evident from the variant type and in silico pathogenicity prediction does not add independent evidence. Per PMC6185798, PP3 should not be stacked with PVS1 for variants where the deleterious mechanism is already captured by the variant type. Details ▾Hide ▴
Evidence considered
- BayesDel score 0.66 noted but not applicable to PP3 for a truncating variant
- SpliceAI max delta 0.14 confirms no cryptic splice effect
BP4 N/ABP4 evaluates in silico predictions suggesting no impact for missense or splice variants. This is a nonsense variant where the protein-truncating effect is self-evident; in silico tools are not designed to assess stop-gain variants. SpliceAI max delta score of 0.14 indicates no cryptic splice effect, but BP4 does not apply to nonsense variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.14 indicates no significant splice alteration
- BayesDel 0.66 not applicable to nonsense variant assessment
BP7 N/AThis is a nonsense variant. BP7 applies to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). BayesDel score = 0.66.
5 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 9643284 ↗Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations.Genotype-phenotype study of 125 NF2 families demonstrating that truncating mutations (nonsense, frameshift) are associated with significantly earlier age of onset (mean 19 years) and more severe disease compared to missense, splice site, and large deletion mutations. Table 2 catalogues 60 NF2 mutations including nonsense mutations in nearby codons (e.g., Arg196Ter, Arg198Ter) but does not include p.Glu202Ter (c.604G>T). The variant p.Glu202Ter was not identified among the listed mutations.→ PM1 Does not name this variant
Source detail
Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001).
Location Table 2 (complete mutation listing) — variant not present
Other recorded publications
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PMID 19545378 ↗Neurofibromatosis type 2 (NF2): a clinical and molecular review.Comprehensive clinical and molecular review of neurofibromatosis type 2 (NF2). Discusses NF2 epidemiology, diagnostic criteria, genotype-phenotype correlations, and the merlin tumor suppressor pathway at the gene level. The specific variant p.Glu202Ter (c.604G>T) was not identified in this review.Does not name this variant
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PMID 22825583 ↗New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment.Reviews the role of NF2 and BAP1 somatic inactivation in malignant pleural mesothelioma (MPM) and discusses mTOR pathway as a therapeutic target downstream of merlin loss. Focuses on somatic NF2 mutations in MPM, not germline variants. The specific variant p.Glu202Ter was not identified in this paper.Does not name this variant
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PMID 8755919 ↗Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease.Reports that the type of NF2 mutation frequently determines disease severity, with truncating mutations causing more severe disease than missense mutations. Full text was not available for review; abstract describes general genotype-phenotype correlation without specifying individual variants. The specific variant p.Glu202Ter was not identified in the abstract.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. This is a clinical practice guideline, not a variant-level publication. Does not discuss any specific NF2 variants. The specific variant p.Glu202Ter was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.140
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000268.3%3Ac.604G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-30054182-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-29658193-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/22-29658193-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000268.3%3Ac.604G…
- OncoKB ↗www.oncokb.org/gene/NF2/E202*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=131821833
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). BayesDel score = 0.66.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58526910, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.